Natural immunity can inhibit the development of a tumor cell during carcinogenesis as evidenced by cytostatic and cytocidal assays during chemical carcinogen induction of neoplastic transformation in cultured mammalian cells. Natural cytotoxic activity of normal unstimulated nonimmune macrophages and lymphocyte populations for tumor cells is quantifiable by lymphoid effector cell-mediated inhibition of tumor cell colony formation and release of radionuclides. Lymphotoxin, one of the lymphokines, soluble mediators of immunoregulatory function, also exhibits cytotoxicity for tumor cells not observed with nontumorigenic cells. In in vitro models of carcinogenesis, such as neoplastic transformation of guinea pig cells, where distinct discrete stages in carcinogenesis can be readily identified and studied, susceptibility to natural immunocytotoxicity develops concomitantly or in close association with neoplastic transformation. Neoplastic cells, but not their nontumorigenic counterparts, also exhibit delayed hypersensitivity skin reactions in normal nonimmune syngeneic animals. This natural skin reactivity, like natural immunocytotoxicity, is independent of cell surface tumor-specific transplantation rejection antigens yet is individually distinctive for each tumor cell line.